Leal Ana S, Moerland Jessica A, Zhang Di, Carapellucci Sarah, Lockwood Beth, Krieger-Burke Teresa, Aleiwi Bilal, Ellsworth Edmund, Liby Karen T
Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI 48824, USA.
In Vivo Facility, Michigan State University, East Lansing, MI 48824, USA.
Cancers (Basel). 2021 Oct 6;13(19):5004. doi: 10.3390/cancers13195004.
(1) Background: Notwithstanding numerous therapeutic advances, 176,000 deaths from breast and lung cancers will occur in the United States in 2021 alone. The tumor microenvironment and its modulation by drugs have gained increasing attention and relevance, especially with the introduction of immunotherapy as a standard of care in clinical practice. Retinoid X receptors (RXRs) are members of the nuclear receptor superfamily and upon ligand binding, function as transcription factors to modulate multiple cell functions. Bexarotene, the only FDA-approved RXR agonist, is still used to treat cutaneous T-cell lymphoma. (2) Methods: To test the immunomodulatory and anti-tumor effects of MSU42011, a new RXR agonist, we used two different immunocompetent murine models (MMTV-Neu mice, a HER2 positive model of breast cancer and the A/J mouse model, in which vinyl carbamate is used to initiate lung tumorigenesis) and an immunodeficient xenograft lung cancer model. (3) Results: Treatment of established tumors in immunocompetent models of HER2-positive breast cancer and Kras-driven lung cancer with MSU42011 significantly decreased the tumor burden and increased the ratio of CD8/CD4, CD25 T cells, which correlates with enhanced anti-tumor efficacy. Moreover, the combination of MSU42011 and immunotherapy (anti-PDL1 and anti-PD1 antibodies) significantly ( < 0.05) reduced tumor size vs. individual treatments. However, MSU42011 was ineffective in an athymic human A549 lung cancer xenograft model, supporting an immunomodulatory mechanism of action. (4) Conclusions: Collectively, these data suggest that the RXR agonist MSU42011 can be used to modulate the tumor microenvironment in breast and lung cancer.
（1）背景：尽管在治疗方面取得了诸多进展，但仅在2021年，美国就有17.6万人死于乳腺癌和肺癌。肿瘤微环境及其药物调节作用受到了越来越多的关注，尤其是随着免疫疗法在临床实践中成为标准治疗方法。视黄酸X受体（RXRs）是核受体超家族的成员，在与配体结合后，作为转录因子发挥作用，调节多种细胞功能。贝沙罗汀是唯一经美国食品药品监督管理局（FDA）批准的RXR激动剂，仍用于治疗皮肤T细胞淋巴瘤。（2）方法：为了测试新型RXR激动剂MSU42011的免疫调节和抗肿瘤作用，我们使用了两种不同的具有免疫活性的小鼠模型（MMTV-Neu小鼠，一种HER2阳性乳腺癌模型和A/J小鼠模型，其中使用氨基甲酸乙烯酯引发肺癌发生）以及一种免疫缺陷的异种移植肺癌模型。（3）结果：用MSU42011治疗HER2阳性乳腺癌和Kras驱动的肺癌免疫活性模型中的已建立肿瘤，显著降低了肿瘤负担，并增加了CD8/CD4、CD25 T细胞的比例，这与增强的抗肿瘤疗效相关。此外，MSU42011与免疫疗法（抗PDL1和抗PD1抗体）联合使用，与单独治疗相比，显著（<0.05）减小了肿瘤大小。然而，MSU42011在无胸腺的人A549肺癌异种移植模型中无效，这支持了其免疫调节作用机制。（4）结论：总体而言，这些数据表明RXR激动剂MSU42011可用于调节乳腺癌和肺癌中的肿瘤微环境。
